Pathophysiology of Transgenic Mouse Models of Huntington's Disease

描述（由申请人提供）：亨廷顿病（HD）中的致死突变是亨廷顿蛋白内的扩增三核苷酸（CAG）重复序列，其最终导致选择性神经变性，特别是在纹状体和皮质内。该提案探讨了HD功能改变的细胞机制。新出现的证据表明，纹状体和皮质神经元和电路的功能障碍发生在疾病表型的发展过程中，早在有显着的细胞损失。纹状体中的形态学变化可能最初由纹状体中型多棘神经元（MSSN）的内在功能特性的改变引发，但最终需要皮质纹状体神经元能输入的异常以表达表型。皮质纹状体通路的功能障碍是复杂的，并且存在多种变化，如与疾病状态的显著年龄相关的短暂和更慢性的相互作用所证明的。越来越多的证据表明，皮质微回路的变化相互作用，诱导皮质纹状体通路功能障碍。关于细胞和电路改变的时间顺序以及纹状体和皮层中选择性神经元脆弱性的原因知之甚少。我们将使用转基因小鼠来解决这些重要问题。该提案将研究发生的功能相互作用，使特定的神经元群体更容易受到功能障碍和随后的变性在HD。我们假设，导致HD功能障碍和病理学的最明显的细胞改变是由细胞-细胞相互作用的组合引起的，而不仅仅是细胞自主变化的结果。我们将测试我们的假设在三个具体的目标，旨在：1。确定电生理特性，使纹状体投射神经元和中间神经元的亚群差异容易受到功能障碍和退化的小鼠模型的HD，2。检查HD小鼠模型大脑皮层兴奋和抑制平衡的改变，这些改变促进并使纹状体和3.检查突变亨廷顿蛋白的广泛表达是否是在已鉴定的MSSN群体中产生差异电生理学改变所必需的。这些研究将为HD的新的合理治疗提供基础，为药物干预划定更多的限制性靶点，也将与了解其他CAG三联重复疾病和神经退行性疾病有关。

DESCRIPTION (provided by applicant): The lethal mutation in Huntington's disease (HD) is an expanded trinucleotide (CAG) repeat within the huntingtin protein which ultimately causes selective neurodegeneration especially within the striatum and cortex. This proposal examines cellular mechanisms underlying functional alterations in HD. Emerging evidence indicates that dysfunctions of striatal and cortical neurons and circuits occur during the development of the disease phenotype, well before there is significant cell loss. Morphological changes in the striatum are probably primed initially by alterations in the intrinsic functional properties of striatal medium- sized spiny neurons (MSSNs), but ultimately require abnormalities in the corticostriatal glutamatergic inputs for the phenotype to be expressed. Malfunctions of the corticostriatal pathway are complex and there are multiple changes as demonstrated by significant age-related transient and more chronic interactions with the disease state. There also is growing evidence for changes in cortical microcircuits that interact to induce dysfunctions of the corticostriatal pathway. Little is known about the temporal sequence of cellular and circuit alterations, as well as the causes of selective neuronal vulnerability in striatum and cortex. We will use genetically-modified mice to address these important questions. This proposal will examine the functional interactions that occur to make specific neuronal populations more vulnerable to dysfunction and subsequent degeneration in HD. We hypothesize that the most conspicuous cellular alterations leading to dysfunction and pathology in HD result from a combination of cell-cell interactions and are not solely the outcome of cell- autonomous changes. We will test our hypothesis in three specific aims designed to: 1. Determine the electrophysiological properties that make subpopulations of striatal projection neurons and interneurons differentially vulnerable to dysfunction and degeneration in mouse models of HD, 2. Examine the alterations in the balance of excitation and inhibition in the cerebral cortex of mouse models of HD that facilitate and enable abnormalities in the striatum and 3. Examine if widespread expression of mutant huntingtin is necessary to produce differential electrophysiological alterations in identified populations of MSSNs. These studies will provide the basis for novel rational treatments of HD by delineating more restricted targets for drug intervention and also will be relevant for understanding other CAG triplet repeat diseases and neurodegenerative disorders.